Inhibition of human immunodeficiency virus type 1 replication by blocking IkappaB kinase with noraristeromycin

Journal of Biochemistry
Kaori AsamitsuTakashi Okamoto

Abstract

Nuclear factor kappaB (NF-kappaB) is one of the critical transcription factors in inflammatory responses and replication of viruses such as human immunodeficiency virus (HIV). In fact, it has been demonstrated that various NF-kappaB inhibitors could block HIV replication. To explore more potent NF-kappaB inhibitors, we focused on carbocyclic adenine nucleosides that had been reported to have anti-inflammatory effects. We synthesized 15 carbocyclic adenine nucleoside compounds and examined their effects on the NF-kappaB-dependent gene expression using HEK293 cell line. Among these compounds, noraristeromycin (NAM) exhibited the most potent inhibitory effect on the NF-kappaB activity under the non-cytotoxic concentrations. NAM-inhibited IkappaBalpha phosphorylation and degradation upon stimulation of cells with tumour necrosis factor-alpha (TNF-alpha). In addition, NAM prevented p65 phoshorylation. These findings suggested that both IkappaB kinase-alpha (IKK-alpha) and -beta were targeted by NAM. Interestingly, in vitro kinase assay revealed that NAM inhibited the kinase activity of IKK-alpha more potently than that of IKK-beta. When we treated the cell lines, OM10.1 and Molt4/IIIB, in which HIV-1 is latently and chronically infe...Continue Reading

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Citations

Nov 15, 2011·AIDS Research and Human Retroviruses·Ann Florence B Victoriano, Takashi Okamoto
Jan 1, 2012·Biology·Guillaume Mousseau, Susana Valente
Jul 30, 2011·British Journal of Pharmacology·Carly GambleAndrew Paul
Nov 19, 2013·Pharmaceutical Patent Analyst·Sabin Llona-MinguezSimon P Mackay
Jun 13, 2012·Tetrahedron Letters·Quachel BazileJunyan Zhong

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